It is well known that disease activity is significantly reduced during late pregnancy in women with multiple sclerosis (MS). This disease-modifying effect is far more powerful than any existing treatments for MS. There are no studies of pregnant women with MS to investigate the underlying mechanisms responsible for this effect. Based on our studies of the disease-modifying effect of pregnancy in the animal model of MS, experimental allergic encephalomyelitis, we hypothesize that there is a circulating factor present during late pregnancy that suppresses activation of memory CD4+ T cells and accounts for the disease amelioration in pregnant women with MS. We will test this hypothesis first by characterizing the state of T cell activation in MS patients during pregnancy and for 1-year postpartum using 11-color FACS analysis of peripheral blood mononuclear cells. Secondly, we will determine if the changes in antigen-specific memory T cell activation are different in women with MS as compared with healthy pregnant women (n = 20). This will address the important question of whether an underlying defect in pregnancy-related hormonal regulation of the immune system is key in the pathogenesis of MS. Finally, we will test (in vitro) the effect of human pregnancy sera on alterations in Th1-like memory T cells and compare this with the ex vivo measurements of memory T cell function during pregnancy in women with MS. To address these aims, we will enroll pregnant women with MS (n = 50) and healthy pregnant women (n = 20). Clinical information will be collected prospectively by the participants? neurologist and from medical records and interviewer-administered questionnaires in early pregnancy, late pregnancy, and at 2, 4, 6 and 12 months postpartum. Statistical analyses of the data will examine the association between the immunologic measures and clinical disease activity while examining (and controlling for) other important factors, such as disease subtype, age, treatment history, and disease duration. The search for the pregnancy-related factor or hormone responsible for the protective effect of pregnancy in MS may potentially lead to the development of novel treatments for MS and other Th1-driven autoimmune diseases.